Biotransformations of Drugs and Chemicals
69
6
Therapeutic Aspects of Drug Metabolism
The magnitude and duration of drug
action is controlled by the extent and
rate of absorption of the drug, the ex-
tent and rate at which it is delivered to
the target site, the extent and rate of
its metabolism, and the rate at which
it
is
cleared
from
the
body.
Factors
that influence the role of metabolism
in determining drug action include ex-
posure to other drugs or xenobiotics,
genetic makeup, gender, diet, age, and
alterations in physiological status. Con-
comitant exposure to a second xenobiotic
can increase the metabolism of a com-
pound by enzyme induction or decrease
its
metabolism
by
enzyme
inhibition.
For example, phenobarbital increases the
metabolism of phenytoin when both are
used in the treatment of epilepsy by in-
ducing cytochrome P450 isoforms that
oxidize phenytoin.
The genetic makeup of the individual
is important because the levels of indi-
vidual drug-metabolizing enzymes in the
human population are genetically deter-
mined. Gender and physiological status
are important because hormonal factors
alter, among other parameters, the levels
and types of drug-metabolizing enzymes.
Thepro±leofdrug-metabolizingenzymes
is thus determined by a combination of
heredity and environment and varies from
individual to individual.
7
Species Differences and Extrapolation to
Humans
In
view
of
the
sensitivity
of
drug-
metabolizing systems to genetic and en-
vironmental factors, it is not surpris-
ing that there are major differences in
the metabolism of xenobiotics by dif-
ferent species. The species-dependence
of
drug
metabolism
is
a
major
con-
cern in the extrapolation to humans of
metabolic, pharmacokinetic, and toxico-
logical data obtained with animals. In-
terspecies variability involves xenobiotic
absorption, distribution, and excretion as
well as metabolism. Unfortunately, no sin-
gle animal is a reliable mimic of drug
metabolism in humans, although on the
average the rhesus monkey is probably
one of the better mimics. For example,
glucuronidation is a negligible metabolic
pathway for oxaprozin in rats, but accounts
for roughly half of the total metabolic prod-
ucts in rhesus monkeys and man (Fig. 17).
It is not uncommon, however, for other
species to predict the metabolism of spe-
ci±c xenobiotics via individual pathways
N
O
HO
2
C
Oxaprozin
N
O
O
HO
HO
OH
CO
2
H
H
O
O
Fig. 17
Glucuronidation of oxaprozin is a major pathway of metabolism in humans
and rhesus monkeys but not in rats.
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